Is ABCA4 p.Ala1255Val (c.3764C>T) pathogenic?

ABCA4 p.Ala1255Val (c.3764C>T) is classified Uncertain significance in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-24). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.015%, amr).

How common is ABCA4 p.Ala1255Val (c.3764C>T) in the general population?

ABCA4 p.Ala1255Val (c.3764C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ABCA4 p.Ala1255Val (c.3764C>T)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

ABCA4 p.Ala1255Val

c.3764C>T · rs762125655 · VCV962375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.29, phastCons 0.96
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	17.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,010 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.00062% 10/1,614,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA4
Protein: p.Ala1255Val
Coding: c.3764C>T
MANE Select: NM_000350
dbSNP: rs762125655
Type: single nucleotide variant
Location: chr1:94037194 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1255: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (found in a patient with macular dystrophy; uncertain significance); a turn; a disulfide bond

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA4 c.1937+1G>A Pathogenic ★★★ same type
ABCA4 c.3328+2T>A Pathogenic ★★★ same type
ABCA4 c.3523-1G>A Pathogenic ★★★ same type
ABCA4 c.4253+43G>A Pathogenic ★★★ same type
ABCA4 c.4254-1G>C Pathogenic ★★★ same type
ABCA4 c.4352+1G>A Pathogenic ★★★ same type
ABCA4 c.4773+3A>G Pathogenic ★★★ same type
ABCA4 c.5018+2T>A Pathogenic ★★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca4-p-ala1255val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown